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Unfolding of the Amyloid β-Peptide Central Helix: Mechanistic Insights from Molecular Dynamics Simulations

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  • Mika Ito
  • Jan Johansson
  • Roger Strömberg
  • Lennart Nilsson

Abstract

Alzheimer's disease (AD) pathogenesis is associated with formation of amyloid fibrils caused by polymerization of the amyloid β-peptide (Aβ), which is a process that requires unfolding of the native helical structure of Aβ. According to recent experimental studies, stabilization of the Aβ central helix is effective in preventing Aβ polymerization into toxic assemblies. To uncover the fundamental mechanism of unfolding of the Aβ central helix, we performed molecular dynamics simulations for wild-type (WT), V18A/F19A/F20A mutant (MA), and V18L/F19L/F20L mutant (ML) models of the Aβ central helix. It was quantitatively demonstrated that the stability of the α-helical conformation of both MA and ML is higher than that of WT, indicating that the α-helical propensity of the three nonpolar residues (18, 19, and 20) is the main factor for the stability of the whole Aβ central helix and that their hydrophobicity plays a secondary role. WT was found to completely unfold by a three-step mechanism: 1) loss of α-helical backbone hydrogen bonds, 2) strong interactions between nonpolar sidechains, and 3) strong interactions between polar sidechains. WT did not completely unfold in cases when any of the three steps was omitted. MA and ML did not completely unfold mainly due to the lack of the first step. This suggests that disturbances in any of the three steps would be effective in inhibiting the unfolding of the Aβ central helix. Our findings would pave the way for design of new drugs to prevent or retard AD.

Suggested Citation

  • Mika Ito & Jan Johansson & Roger Strömberg & Lennart Nilsson, 2011. "Unfolding of the Amyloid β-Peptide Central Helix: Mechanistic Insights from Molecular Dynamics Simulations," PLOS ONE, Public Library of Science, vol. 6(3), pages 1-13, March.
  • Handle: RePEc:plo:pone00:0017587
    DOI: 10.1371/journal.pone.0017587
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    References listed on IDEAS

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    1. Tara Hessa & Hyun Kim & Karl Bihlmaier & Carolina Lundin & Jorrit Boekel & Helena Andersson & IngMarie Nilsson & Stephen H. White & Gunnar von Heijne, 2005. "Recognition of transmembrane helices by the endoplasmic reticulum translocon," Nature, Nature, vol. 433(7024), pages 377-381, January.
    2. Fabrizio Chiti & Massimo Stefani & Niccolò Taddei & Giampietro Ramponi & Christopher M. Dobson, 2003. "Rationalization of the effects of mutations on peptide andprotein aggregation rates," Nature, Nature, vol. 424(6950), pages 805-808, August.
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    Cited by:

    1. Payel Das & Seung-gu Kang & Sally Temple & Georges Belfort, 2014. "Interaction of Amyloid Inhibitor Proteins with Amyloid Beta Peptides: Insight from Molecular Dynamics Simulations," PLOS ONE, Public Library of Science, vol. 9(11), pages 1-21, November.

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